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CKIP-1 acts downstream to Cx43 on the activation of Nrf2 signaling pathway to protect from renal fibrosis in diabetes.
- Source :
-
Pharmacological research [Pharmacol Res] 2021 Jan; Vol. 163, pp. 105333. Date of Electronic Publication: 2020 Dec 01. - Publication Year :
- 2021
-
Abstract
- We previously reported that both Cx43 and CKIP-1 attenuated diabetic renal fibrosis via the activation of Nrf2 signaling pathway. However, whether CKIP-1, a scaffold protein, participates in regulating the activation of Nrf2 signaling pathway by Cx43 remains to be elucidated. In this study, the effect of adenovirus-mediated Cx43 overexpression on renal fibrosis in CKIP-1 <superscript>-/-</superscript> diabetic mice was investigated. We found that overexpression of Cx43 could significantly alleviate renal fibrosis by activating the Nrf2 pathway in diabetic mice, but have no obvious effect in CKIP-1 <superscript>-/-</superscript> diabetic mice. Cx43 overexpressed plasmid and CKIP-1 small interfering RNA were simultaneously transfected into glomerular mesangial cells and the result demonstrated that the effect of activation of Nrf2 signaling pathway by Cx43 was blocked by CKIP-1 depletion. The interaction between Cx43 and CKIP-1 was analyzed by immunofluorescence and immunoprecipitation assays. We found that Cx43 interacted with CKIP-1, and the interaction was weakened by high glucose treatment. Moreover, Cx43 regulated the expression of CKIP-1 and the interaction of CKIP-1 with Nrf2 via Cx43 carboxyl terminus (CT) domain, thereby activating Nrf2 signaling pathway. According to the results, we preliminary infer that CKIP-1 acts downstream to CX43 on the activation of Nrf2 signaling pathway to protect from renal fibrosis in diabetes, the mechanism of which might be related to the interaction of CKIP-1 with Nrf2 through Cx43 CT. Our study provides further experimental basis for targeting the Cx43-CKIP-1-Nrf2 axis to resist diabetic renal fibrosis.<br /> (Copyright © 2020 Elsevier Ltd. All rights reserved.)
- Subjects :
- Animals
Carrier Proteins genetics
Cells, Cultured
Connexin 43 genetics
Diabetes Mellitus, Experimental pathology
Diabetic Nephropathies pathology
Diabetic Nephropathies prevention & control
Fibrosis
Hydrogen Peroxide metabolism
Kidney metabolism
Kidney pathology
Male
Mesangial Cells metabolism
Mice, Inbred C57BL
Mice, Knockout
Rats, Sprague-Dawley
Signal Transduction
Superoxides metabolism
Mice
Rats
Carrier Proteins metabolism
Connexin 43 metabolism
Diabetes Mellitus, Experimental metabolism
Diabetic Nephropathies metabolism
NF-E2-Related Factor 2 metabolism
Subjects
Details
- Language :
- English
- ISSN :
- 1096-1186
- Volume :
- 163
- Database :
- MEDLINE
- Journal :
- Pharmacological research
- Publication Type :
- Academic Journal
- Accession number :
- 33276097
- Full Text :
- https://doi.org/10.1016/j.phrs.2020.105333